Characterization of Platelet Function in Patients with Bleeding Disorders: In FY2011 (the third year of this project) we have studied several patients with suspected or documented disorders of platelet function and have identified patients with deficiency of dense granules (storage pool disease), and characterized platelet function in people with congenital or acquired platelet dysfunction. The ability to make a reliable, detailed characterization of platelet function may help investigators who are studying genetics of inherited platelet disorders. Characterization of D-Dimer and Related Coagulation Proteins in HIV-Infected Research Subjects Undergoing IL-2 Therapy: During the third year of this project, in support of intramural NIH research protocols, we have measured D-dimer levels and numerous coagulation parameters in research subjects who are infected with HIV or who are normal volunteers. We seek to correlate the D-dimer levels with these various parameters to gain insights into the mechanism for the observed elevations in D-dimer levels in HIV infected patients that correlate with increased morbidity and mortality. Markers of Endothelial Cell Injury and Thrombosis in Patients Undergoing Cancer Chemotherapy. During the second year of this project, in support of intramural NIH research protocols, we measured various markers of thrombosis (prothrombin fragment 1.2, D-dimer, thrombin-antithrombin complexes, tissue factor, sVCAM, thrombomodulin, E-selectin, etc.) in chronic lymphocytic leukemia (CLL) that were treated with the thalidomide derivative revlimid. Some of these patients developed DVT while on the study. Our findings (published in the American Journal of Hematology) are that thrombomodulin and sVCAM elevations correspond to TNFalpha cytokine elevations in the patients with DVT. In CLL patients treated with ibrutinib, we have noted a significant increase in platelet count and a significant decrease in von Willebrand factor levels in the 28 day period after initiation of treatment. This appears to be independent of the WBC count, a surrogate for clinical response. Effect of Factor VIII Haplotypes on Inhibitor Development. We have identified a set of 800 DNA samples from patients with severe hemophilia A in an NHLBI repository and have IRB approval to determine their factor VIII protein-coding polymorphisms to determine the effect of factor VIII haplotype on inhibitor development. We expect to complete the DNA sequence determinations in the coming fiscal year, and will see if the effect of protein coding polymorphisms on inhibitor development that was seen in a minority population (African-Americans) can be seen in the population as a whole.